Drug discovery in the next decade: innovation needed ASAP
Drug discovery in the next decade: innovation needed ASAP
Drug discovery in the next decade: innovation needed ASAP
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<strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011REVIEWSCulture of <strong>in</strong>novation-<strong>ASAP</strong> (i<strong>ASAP</strong>): Ask powerful questions;Seek <strong>the</strong> outliers; Accept defeat; Populate astutely.<strong>Drug</strong> <strong>discovery</strong> <strong>in</strong> <strong>the</strong> <strong>next</strong> <strong>decade</strong>:<strong>in</strong>novation <strong>needed</strong> <strong>ASAP</strong>Reviews KEYNOTE REVIEWYoussef L. BennaniVertex Pharmaceuticals, 130 Waverly St., Cambridge, MA 02139, USAPharmaceutical companies must f<strong>in</strong>d a better way to <strong>in</strong>crease <strong>the</strong>ir outputof truly new drugs for <strong>the</strong> benefit of patients and for <strong>the</strong>ir bus<strong>in</strong>ess survival.Here, I highlight a general perspective from with<strong>in</strong> pharmaceuticalresearch as it perta<strong>in</strong>s to research advances <strong>in</strong> chemistry, biology,pharmacology, pharmacok<strong>in</strong>etics and toxicology that, if well <strong>in</strong>tegrated,stands to put <strong>the</strong> <strong>in</strong>dustry on a productive path. In addition, I provide acomplementary perspective on <strong>the</strong> corporate culture aspect of <strong>in</strong>novation.I also <strong>in</strong>troduce a new concept, termed ‘<strong>in</strong>novation <strong>ASAP</strong>’ (i<strong>ASAP</strong>; ask<strong>in</strong>gpowerful questions, seek<strong>in</strong>g <strong>the</strong> outliers, accept<strong>in</strong>g defeat and populat<strong>in</strong>gastutely) and provide support for it us<strong>in</strong>g examples of several successfuldrugs.YOUSSEFL. BENNANIYoussef L. Bennaniobta<strong>in</strong>ed his undergraduate(BSc) and graduatedegrees (MSc and PhD)<strong>in</strong> chemistry from <strong>the</strong>Universite de Montreal,under <strong>the</strong> guidance ofProfessor StephenHanessian, andconducted post-doctoral studies at The ScrippsResearch Institute with Professor K. Barry Sharpless.He also holds an MBA from Lake Forest GraduateSchool of Management. In 1993, he jo<strong>in</strong>ed <strong>the</strong> pharmaceutical<strong>in</strong>dustry, as a researcher, work<strong>in</strong>g forLigand Pharmaceuticals, Abbott Laboratories andA<strong>the</strong>rsys Inc. He currently serves as Vice President of<strong>Drug</strong> Innovation at Vertex Pharmaceuticals, head<strong>in</strong>gboth <strong>the</strong> <strong>discovery</strong> chemistry and pharmacok<strong>in</strong>eticsdepartments. He has led programs <strong>in</strong> immunology,oncology, neurology, metabolic and <strong>in</strong>fectious diseases,result<strong>in</strong>g <strong>in</strong> numerous precl<strong>in</strong>ical and cl<strong>in</strong>icalmolecular entities; and has published over 170 papersand patents <strong>in</strong> <strong>the</strong> field of drug <strong>discovery</strong>.IntroductionThe pharmaceutical sector, a cornerstone of <strong>the</strong> healthcare <strong>in</strong>dustry, is undergo<strong>in</strong>g dramaticchange, primarily caused by reduced output of new medic<strong>in</strong>es from research and development(R&D) laboratories, drug pric<strong>in</strong>g pressures, stricter regulatory environments and <strong>the</strong> overallcurrent economic downturn. This makes demands of all pharmaceutical companies to f<strong>in</strong>dbetter ways to <strong>in</strong>crease <strong>the</strong>ir output of new drugs, through <strong>in</strong>novation, to both treat patients andmeet <strong>the</strong>ir shareholders’ expectations.This article highlights a general perspective from with<strong>in</strong> pharmaceutical research as it perta<strong>in</strong>sto research advances <strong>in</strong> drug <strong>discovery</strong> [<strong>in</strong>clud<strong>in</strong>g chemistry, biology, pharmacology, pharmacok<strong>in</strong>etics(PK) and toxicology] and offers a complementary perspective on <strong>the</strong> corporate cultureaspects of <strong>in</strong>novation. A new concept, termed ‘<strong>in</strong>novation <strong>ASAP</strong>’ (i<strong>ASAP</strong>: ask<strong>in</strong>g powerfulquestions, seek<strong>in</strong>g <strong>the</strong> outliers, accept<strong>in</strong>g defeat and populat<strong>in</strong>g astutely) is <strong>in</strong>troduced andsupported by several successful examples <strong>in</strong> drug <strong>discovery</strong> and bus<strong>in</strong>ess <strong>in</strong> general. The goal ofthis article is to add value to all ongo<strong>in</strong>g efforts aimed at <strong>in</strong>novation <strong>in</strong> medic<strong>in</strong>e, as a potentialdriver to revive both <strong>the</strong> healthcare sector and contribute to <strong>the</strong> economy <strong>in</strong> general.The current state of <strong>the</strong> pharmaceutical <strong>in</strong>dustry is undeniably dour. A comb<strong>in</strong>ation of fall<strong>in</strong>gsuccess rates <strong>in</strong> <strong>the</strong> development of <strong>in</strong>novative <strong>the</strong>rapeutics, pend<strong>in</strong>g patent expirations for majordrug classes, <strong>in</strong> addition to <strong>the</strong> conditions stated above, have created a perfect storm for <strong>the</strong><strong>in</strong>dustry [1–5]. This has resulted <strong>in</strong>: (i) <strong>in</strong>creas<strong>in</strong>g rates of mergers and acquisitions; (ii) strategicshifts toward generics and emerg<strong>in</strong>g markets; (iii) dramatic numbers of job losses over <strong>the</strong> pastE-mail address: youssef_bennani@vrtx.com.1359-6446/06/$ - see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2011.06.004 www.drug<strong>discovery</strong>today.com 779
REVIEWS <strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011Reviews KEYNOTE REVIEWthree years; and (iv) rapid shifts toward <strong>the</strong> use of lower-costcontract research organizations (CROs) <strong>in</strong> all aspects of <strong>the</strong> <strong>in</strong>dustry(research, development, manufactur<strong>in</strong>g, among o<strong>the</strong>rs),coupled with a trend toward decreas<strong>in</strong>g <strong>in</strong>ternal R&D budgets.This latter po<strong>in</strong>t is of timely importance, because <strong>the</strong> use ofexternal R&D support tends to perpetuate <strong>the</strong> same approachesor strategies that got <strong>the</strong> <strong>in</strong>dustry <strong>in</strong>to this state of affairs <strong>in</strong> <strong>the</strong> firstplace, and does not <strong>in</strong>volve a real new strategy toward <strong>in</strong>novativeproducts. The claimed lower costs, through CROs, might not betruly value add<strong>in</strong>g, because outsourced full-time employees comeat a higher cost of management and <strong>the</strong> potential loss of anopportunity to <strong>in</strong>novate. As Tom Peters states: ‘You can’t shr<strong>in</strong>kyour way to greatness’ [6]. F<strong>in</strong>ally, <strong>the</strong> image of <strong>the</strong> pharmaceutical<strong>in</strong>dustry, as a well-respected bus<strong>in</strong>ess that improves health, hasbeen tarnished by price <strong>in</strong>creases as well as news reports of medical,market<strong>in</strong>g and political lobby<strong>in</strong>g, and direct-to-consumermarket<strong>in</strong>g, all result<strong>in</strong>g <strong>in</strong> record f<strong>in</strong>es [7].More po<strong>in</strong>tedly, by chas<strong>in</strong>g ‘low-hang<strong>in</strong>g fruit’, target-basedpharmaceutical research has forced most companies to competeon similar targets and approaches, result<strong>in</strong>g <strong>in</strong> duplicative andnonproductive <strong>in</strong>vestments. F<strong>in</strong>ally, it appears as though previous<strong>in</strong>vestments <strong>in</strong> high throughput screen<strong>in</strong>g (HTS), comb<strong>in</strong>atorialchemistry, genomics and proteomics over <strong>the</strong> past two <strong>decade</strong>s(<strong>the</strong> very technologies that were supposed to keep <strong>the</strong> <strong>in</strong>dustryfrom <strong>the</strong> abyss) have yielded a low return on <strong>in</strong>vestment. Arguably,<strong>the</strong>se perfect storm conditions also provide numerous opportunitiesand rem<strong>in</strong>d <strong>the</strong> <strong>in</strong>dustry that necessity is <strong>the</strong> mo<strong>the</strong>r of<strong>in</strong>vention.On <strong>the</strong> brighter side, over <strong>the</strong> past two <strong>decade</strong>s, <strong>the</strong> pharmaceutical<strong>in</strong>dustry has produced some remarkable medic<strong>in</strong>es to treatseveral conditions, rang<strong>in</strong>g from human immune deficiency virus<strong>in</strong>fections (HIV) to cardiovascular diseases (CVD), result<strong>in</strong>g <strong>in</strong>reduced mortality rates, and rheumatoid arthritis through antitumornecrosis factor (anti-TNF) biologics, to name just a few.Additionally, from <strong>the</strong> research scientific and operations standpo<strong>in</strong>t,much progress has been achieved <strong>in</strong> key areas of drug<strong>discovery</strong>, despite <strong>the</strong> perceived notion of <strong>the</strong> opposite. Suchadvances, if well <strong>in</strong>tegrated, will counter this downturn and setdrug <strong>discovery</strong> on a more productive and successful course. Here, Iprovide a look forward and offer possible solutions toward a more<strong>in</strong>tegrative, <strong>in</strong>novative and, probably more productive R&D environment.So, how can <strong>the</strong> <strong>in</strong>dustry claw its way back from <strong>the</strong> edge?In chaos lies opportunityA recent survey of <strong>the</strong> top 25 most <strong>in</strong>novative companies, encompass<strong>in</strong>gall types of bus<strong>in</strong>ess, did not <strong>in</strong>clude a s<strong>in</strong>gle pharmaceuticalor biotechnology company (http://images.bus<strong>in</strong>essweek.com/ss/10/04/0415_most_<strong>in</strong>novative_companies/<strong>in</strong>dex.htm).However, a survey of <strong>the</strong> top 20 most <strong>in</strong>novative pharmaceuticalor medical device companies, and endorsed by Wall Street, showeda strong correlation between <strong>the</strong> value creation of a product, asmeasured by market capitalization, and its novelty, as measured byclear cl<strong>in</strong>ical and market superiority (http://www.<strong>in</strong>novaro.com/pressReleaseFiles/Innovation%20Index%202010%20Q2%205-11-10.pdf). These reported rank<strong>in</strong>gs are argued to be a cleardemonstration of <strong>the</strong> demise of <strong>the</strong> blockbuster bus<strong>in</strong>ess model, ascurrently practiced by large pharmaceutical companies, given howsparsely <strong>the</strong>se large companies are listed amongst <strong>the</strong> top 20<strong>in</strong>novators. From <strong>the</strong>se reports, it is evident that <strong>the</strong> most <strong>in</strong>novativecompanies, and thus <strong>the</strong> most value-creat<strong>in</strong>g ones, are thosethat master <strong>the</strong> art (and science) of understand<strong>in</strong>g necessity ra<strong>the</strong>rthan creat<strong>in</strong>g it. Perhaps that it is <strong>the</strong> multitude of ‘follow-on’s’ or‘me-too’s’ to <strong>the</strong> blockbuster drugs that are <strong>the</strong> culprit (vide <strong>in</strong>fra).To set <strong>the</strong> stage for a discussion on <strong>in</strong>novation, a def<strong>in</strong>ition isnecessary. There are many ways to def<strong>in</strong>e <strong>in</strong>novation but, <strong>in</strong>essence, it is ‘ideas that ship out’, as such l<strong>in</strong>k<strong>in</strong>g fresh th<strong>in</strong>k<strong>in</strong>gto f<strong>in</strong>al products. O<strong>the</strong>rs def<strong>in</strong>e it as ‘a new match between a needand a solution’, where <strong>the</strong> novelty can be ei<strong>the</strong>r <strong>in</strong> <strong>the</strong> solution or<strong>the</strong> need (all depend<strong>in</strong>g on how one def<strong>in</strong>es need); or <strong>in</strong> a newmarriage of <strong>the</strong> two [8]. From <strong>the</strong> <strong>in</strong>novation–valuation standpo<strong>in</strong>t,one could def<strong>in</strong>e <strong>the</strong> result of <strong>in</strong>novation as product orservice that both enables a positive return on <strong>in</strong>vestment andcreates susta<strong>in</strong>able valuation for its owners.Arguably, ‘<strong>the</strong> devil is <strong>in</strong> <strong>the</strong> details’ and much high-qualitywork occurs from <strong>the</strong> <strong>in</strong>ception of an idea all <strong>the</strong> way through toproduct packag<strong>in</strong>g. The po<strong>in</strong>t is that identify<strong>in</strong>g <strong>the</strong> right necessityor medical need (every company professes to focus on unmetmedical needs, but it all depends on how that is def<strong>in</strong>ed) andempower<strong>in</strong>g people to work toward that goal, is <strong>the</strong> way forward.So how does one navigate through <strong>the</strong> maze of tribulations, upsand downs all <strong>the</strong> way to value creation?Me-too drugs are failed <strong>in</strong>novationsThe (mega) blockbuster bus<strong>in</strong>ess model has had a profound effecton <strong>the</strong> pharmaceutical <strong>in</strong>dustry, both positive (earn<strong>in</strong>gs) andnegative (culture). Nobody could argue, <strong>in</strong> this capitalistic world,aga<strong>in</strong>st market<strong>in</strong>g a drug to achieve great revenues. Revenueenables fur<strong>the</strong>r <strong>in</strong>vestment, with <strong>the</strong> goal of repeat<strong>in</strong>g an evengreater achievement. Most major pharmaceutical companies haveadopted this paradigm and <strong>in</strong>vested heavily <strong>in</strong> R&D over <strong>the</strong> pasttwo <strong>decade</strong>s, more so than any o<strong>the</strong>r <strong>in</strong>dustry as a percentage ofsales [9]. This approach has forced R&D-<strong>in</strong>tensive companies tofocus ma<strong>in</strong>ly on opportunities with >US$ 1 billion annual marketpotential, which, <strong>in</strong> return, has created bl<strong>in</strong>d spots toward manydiseases and perceived medical needs that did not meet <strong>the</strong>sereturn levels. In addition, it tended to attract several players <strong>in</strong>tosimilar markets, which led to many years of heavy <strong>in</strong>vestments todemonstrate cl<strong>in</strong>ical non-<strong>in</strong>feriority or marg<strong>in</strong>al superiority toga<strong>in</strong> Food and <strong>Drug</strong> Adm<strong>in</strong>istration (FDA) approval. The currenttrend to catch <strong>the</strong> current biologics or bio-similar(s) wave, couldwell backfire <strong>in</strong> a similar way to small-molecule follow-onapproaches, over <strong>the</strong> <strong>next</strong> few <strong>decade</strong>s. Fur<strong>the</strong>rmore, commercialfunctions have been <strong>in</strong> <strong>the</strong> driver’s seat <strong>in</strong> cl<strong>in</strong>ical trial design,which has led to a bus<strong>in</strong>ess- ra<strong>the</strong>r than science-led cl<strong>in</strong>ical trialapproach, often lead<strong>in</strong>g to failure. Although large revenues weresometimes achieved through this model, it seems to have led <strong>the</strong><strong>in</strong>dustry to <strong>the</strong> edge of a cliff, given how difficult it has been toreproduce it rout<strong>in</strong>ely [10]. The argument is that <strong>the</strong> bus<strong>in</strong>essoperates <strong>in</strong> <strong>the</strong> ‘outlier space’ and repeats are rare. So, what is anoperationally viable new bus<strong>in</strong>ess model for <strong>the</strong> <strong>next</strong> cycle?Revenue versus value creation<strong>Drug</strong> classes that work through similar general mechanisms, suchas stat<strong>in</strong>s (e.g. Lipitor 1 , Zocor 1 , Crestor 1 , Vytor<strong>in</strong> 1 , Lescol 1 andCaduet 1 ), antiulcerants (e.g. Nexium 1 /Losec 1 , Takepron 1 , Rabeprazole1 and Protonix 1 ) and antipsychotics (e.g. Seroquel 1 ,780 www.drug<strong>discovery</strong>today.com
<strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011[(Figure_1)TD$FIG]REVIEWS(a) HOF(b)OOOHHNNOHNHNSOOLipitor®Component of Caduet®NOFHONNHOOHOHN NNOSOCrestor®SOONOFFOFHOOHNNOHOHNLescol®SOONOHNNOOH OSOOHNOZocor®Component of Vytor<strong>in</strong>®Nexium® Rabeprazole® PANTOPRAZOLE® Takepron/Lansoprazole®OFFReviews KEYNOTE REVIEW(c)FONOHNNOSNNN NNNNNONHNONOSN SNN CIHNHSeroquel® Zyprexa® Risperidone® Zeldox® OAbilify®CICI<strong>Drug</strong> Discovery TodayFIGURE 1Representative drugs from <strong>the</strong> stat<strong>in</strong> (a), antiulcerant (b) and antipsychotic (c) classes.Zyprexa 1 , Risperidone 1 , Abilify 1 and Zeldox 1 ; Fig. 1), garneredalmost US$ 25 billion, US$ 20 billion and US$ 20 billion <strong>in</strong> salesdur<strong>in</strong>g 2008, respectively. However, dur<strong>in</strong>g <strong>the</strong> period from 2008to <strong>the</strong> present, <strong>the</strong> very companies that sell <strong>the</strong>se drugs have seen<strong>the</strong>ir valuations drop by 20–40% (relatively similar trends for mostbig pharmaceutical companies apply from 2001 to 2010). I do notwish or need to highlight any particular company <strong>in</strong> regards torevenue versus valuation. However, simple research throughhttp://www.wik<strong>in</strong>vest.com leads to <strong>the</strong> observation that <strong>in</strong>creasedrevenue or gross marg<strong>in</strong>s (over up to 5–10 years) correlate <strong>in</strong>verselywith corporate value creation as measured by lower stock pricesand, thus, lower market capitalization for most large pharmaceuticalenterprises.In o<strong>the</strong>r words, price/earn<strong>in</strong>gs ratios for some of <strong>the</strong> pharmaceuticalcompanies dropped from mid-twenties to high s<strong>in</strong>gledigitlevels. For <strong>the</strong>se companies, catch<strong>in</strong>g up one ano<strong>the</strong>r bycompet<strong>in</strong>g <strong>in</strong> similar markets, ra<strong>the</strong>r than <strong>in</strong>vest<strong>in</strong>g <strong>in</strong> <strong>in</strong>novativeways to treat disease, has clearly back fired. This demonstrates <strong>the</strong>flaws associated with this bus<strong>in</strong>ess model, which has led to <strong>the</strong> lossof several tens of thousand jobs. Many associations exist, where afew products (e.g. Epogen 1 , Avast<strong>in</strong> 1 , Tamiflu 1 , Revlimid 1 , Provigil1 , Depakote 1 and Velcade 1 ; Fig. 2), have driven strong valuecreation for <strong>the</strong>ir respective companies, by virtue of <strong>the</strong>ir uniquenessand, thus, differentiation.It is now undeniable that <strong>in</strong>creased <strong>in</strong>vestments <strong>in</strong> R&D havenot resulted <strong>in</strong> <strong>in</strong>creased numbers of new molecular entities(NMEs). Additionally, recent large-scale phase 3 failures (e.g. Axit<strong>in</strong>ib/Pfizer;Elesclomol/Syntha-GSK; AS404/Antisoma-Novartis;Figitumumab/Pfizer; Iniparib/BiPar-Sanofi; Vandetanib/AstraZeneca;and Torcetrapib/Pfizer) and scarcity of late-stage assets[11], coupled with imm<strong>in</strong>ent patent expirations for mostblockbuster drugs, bode ill for <strong>the</strong> future of research-based pharmaceuticalcompanies, and for <strong>the</strong> <strong>in</strong>dustry as a whole.Innovation <strong>in</strong> drug <strong>discovery</strong> as a survival necessityThe conundrum associated with <strong>in</strong>novation is as follows: youknow that you are <strong>in</strong>novat<strong>in</strong>g, when your supervisor says ‘Areyou crazy’? Or, is it: you know you are ‘crazy’ when your supervisorsays ‘Are you <strong>in</strong>novat<strong>in</strong>g’?Innovation is a necessity for improv<strong>in</strong>g human prosperity andwell-be<strong>in</strong>g. It is imperative that <strong>the</strong> pharmaceutical <strong>in</strong>dustry<strong>in</strong>vests, engages and manages (with a long-term view and commitmentfrom executive management) its resources to ensure thatnew (not ‘me-too’) and value-creat<strong>in</strong>g products emerge from itswww.drug<strong>discovery</strong>today.com 781
<strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011REVIEWSaggregate mastery of all <strong>the</strong> knowledge from <strong>the</strong> above-mentioneddiscipl<strong>in</strong>es, and practical, <strong>in</strong>tegrative use of such acumen that willlead <strong>the</strong> way to truly new medic<strong>in</strong>es. As such, it has a long way to goto address rout<strong>in</strong>ely <strong>the</strong> many pitfalls <strong>in</strong> mov<strong>in</strong>g from a HTS hit to anew chemical entity (NCE), and eventually to marketed NME, <strong>in</strong> afaster and more reliable manner. Conversely, for future majoradvances, practitioners <strong>in</strong> all <strong>the</strong> discipl<strong>in</strong>es mentioned above, willneed to become more knowledgeable <strong>in</strong> areas currently less familiarto <strong>the</strong>m.Numerous examples can be found with<strong>in</strong> R&D organizationswhere a syn<strong>the</strong>tic chemistry, medic<strong>in</strong>al chemistry observation or aformulation breakthrough has added value while creat<strong>in</strong>g a newdrug (my <strong>in</strong>tent here is to highlight <strong>the</strong> topic of observation andquestion<strong>in</strong>g, ra<strong>the</strong>r than conduct an exhaustive list<strong>in</strong>g of valueadd<strong>in</strong>gobservations). This is particularly applicable when solv<strong>in</strong>gaff<strong>in</strong>ity, selectivity, <strong>in</strong> vitro or <strong>in</strong> vivo activity and/or properties,<strong>in</strong>clud<strong>in</strong>g PK or toxicity issues. Examples of <strong>the</strong>se are retrospectiveanalyses of approved drug properties lead<strong>in</strong>g to several rule setsand perspectives, rang<strong>in</strong>g from physicochemical attributes ofdrugs, to formulation sciences and application of cont<strong>in</strong>uousimprovement–efficiency models applied from manufactur<strong>in</strong>gand <strong>in</strong>deed, even to evolv<strong>in</strong>g concepts on ‘druggable’ targets[19–30]. So, how does one move forward <strong>in</strong> medic<strong>in</strong>al chemistry?Biology-based advancesThe conundrum <strong>in</strong> biology is <strong>the</strong> <strong>in</strong>terplay between deductive and<strong>in</strong>ductive biology. Parts of it are well understood and <strong>in</strong>tegratedwith<strong>in</strong> medic<strong>in</strong>al chemistry and drug <strong>discovery</strong>, whereas o<strong>the</strong>rsrema<strong>in</strong> at bay: Deductive biology: where <strong>the</strong> whole is broken down <strong>in</strong>tosmaller bits is well managed <strong>in</strong> current pharmaceutical researchpractice [e.g. gene mapp<strong>in</strong>g, prote<strong>in</strong> production, screen<strong>in</strong>gassays, biochemical readouts, soluble prote<strong>in</strong> structure andstructure-based drug design (SBDD)] [31,32]. Inductive biology: or putt<strong>in</strong>g <strong>the</strong> puzzle back toge<strong>the</strong>r, after aphenotype readout, rema<strong>in</strong>s a mixture of art and science and, assuch, is a fertile area for <strong>in</strong>novation (e.g. membrane andcytosolic prote<strong>in</strong> structural dynamics, signal<strong>in</strong>g nuances,disease biology relevance, compensatory mechanisms and[(Figure_3)TD$FIG] cross-species translation) [33–39].Better tool molecules (e.g. small molecules, peptides, RNA- orprote<strong>in</strong>-based forms) from chemistry or biology will aid <strong>in</strong> fasterand better elucidation of newer disease-relevant f<strong>in</strong>d<strong>in</strong>gs, but only<strong>in</strong> <strong>the</strong> context of improved biological model<strong>in</strong>g of human diseasephysiology. As examples, recent advances <strong>in</strong> G prote<strong>in</strong>-coupledreceptors (GPCR) signal<strong>in</strong>g have begun to offer a glimpse of what ispossible through better appreciation of allosteric modulation[40–42], whereas open–closed states of ion channels [43–47] andprote<strong>in</strong>-fold<strong>in</strong>g dynamics are shap<strong>in</strong>g new understand<strong>in</strong>g of structuralbiology [48]. The emerg<strong>in</strong>g field of stem cell biology, through<strong>the</strong>rapeutics and small-molecule modulation [49], primary humantissue models [50] (normal and pathological) or three-dimensional(3D)-cultures of <strong>the</strong> relevant cell contexts, is likely to boost <strong>the</strong>quest for better medic<strong>in</strong>es. So how is greater precision reached <strong>in</strong><strong>the</strong> biological sciences?PK-based advancesIt is undeniable that better understand<strong>in</strong>g of <strong>the</strong> chemical andpharmaceutical properties of newly syn<strong>the</strong>sized molecules lead<strong>in</strong>gto better PK parameters has had a major effect <strong>in</strong> m<strong>in</strong>imiz<strong>in</strong>g <strong>the</strong>attrition of precl<strong>in</strong>ical and early cl<strong>in</strong>ical molecules. Better <strong>in</strong>tegrationof solubility, cross-species liver microsomal stability, permeabilityand absorption, as well as cross-species metabolism, havebeen well <strong>in</strong>tegrated with<strong>in</strong> <strong>the</strong> medic<strong>in</strong>al chemistry community.As examples, <strong>the</strong> observation that Ritonavir 1 could be used as anexposure booster for Lop<strong>in</strong>avir 1 (and o<strong>the</strong>r drugs) through cytochromeP-450 isoform 3A (CYP3A) <strong>in</strong>hibition; <strong>the</strong> observation of ametabolite of a histam<strong>in</strong>e 1 (H1) blocker with biological activitylead<strong>in</strong>g to Allegra 1 and Zyrtec 1 (Fig. 3), are just a few examples ofask<strong>in</strong>g <strong>the</strong> right questions and <strong>the</strong> power of pharmacologicalobservation. However, prediction of human PK–pharmacodynamic(PKPD) properties has been less than reliable, which po<strong>in</strong>tsto <strong>the</strong> <strong>next</strong> area of endeavor for this area of drug <strong>discovery</strong> [51]. So,how does one raise <strong>the</strong> PKPD sciences to greater predictabilitylevels <strong>in</strong> <strong>the</strong> human sett<strong>in</strong>g?Animal pharmacology-based advancesPractitioners <strong>in</strong> pharmaceutical R&D, and medic<strong>in</strong>al chemists <strong>in</strong>particular, are all familiar with how drugs were <strong>in</strong>vented dur<strong>in</strong>g<strong>the</strong> 1950s through to <strong>the</strong> 1990s. The type of question asked <strong>the</strong>nReviews KEYNOTE REVIEWSOONHHONOONHSNNNHOONHNNHOHONHOHOHOON.HClHOOONNOHClRitonavir® Lop<strong>in</strong>avir® Allegra® Zyrtec®<strong>Drug</strong> Discovery TodayFIGURE 3Representative drugs emerg<strong>in</strong>g from pharmacological observations.www.drug<strong>discovery</strong>today.com 783
REVIEWS <strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011[(Figure_4)TD$FIG]Reviews KEYNOTE REVIEWFONFZetia®OHOHNOO O NSNNHOViagra®CH 3NNCH 3CH 3<strong>Drug</strong> Discovery TodayFIGURE 4Representative drugs emerg<strong>in</strong>g from newer pharmacological or mechanisticobservations.might have <strong>in</strong>cluded (as examples): how can we reverse an epilepticshock? (lead<strong>in</strong>g to Depakote 1 ; Fig. 2) [52]; how can wereduce cholesterol uptake? (lead<strong>in</strong>g to Zetia 1 ) [53]; and <strong>the</strong> fortuitousf<strong>in</strong>d<strong>in</strong>g that led to a weak antihypertensive becom<strong>in</strong>gViagra 1 (Fig. 4), to name but a few [54].In this area, gene knockout technology has provided support<strong>in</strong>gevidence for expected phenotypes and <strong>in</strong>creases confidence <strong>in</strong>particular target <strong>in</strong>vestments [55]. The burgeon<strong>in</strong>g area of biomarkers(previously named phamacogenomics/<strong>in</strong>dividual gene mapp<strong>in</strong>gor personalized medic<strong>in</strong>e; orig<strong>in</strong>ally expected more than tenyears ago) promises to fur<strong>the</strong>r ref<strong>in</strong>e disease biology focus, as wellas enabl<strong>in</strong>g precise and early cl<strong>in</strong>ical readouts and patient stratification<strong>in</strong> cl<strong>in</strong>ical trials [56].However, one key component of animal model-based th<strong>in</strong>k<strong>in</strong>gis <strong>the</strong> admission that we do not know a lot of what we should know(or th<strong>in</strong>k we know): currently, several animal disease models arenot predictive of cl<strong>in</strong>ical outcome [oncology, immunology, centralnervous system (CNS) and o<strong>the</strong>r neurological conditions orpa<strong>in</strong>], whereas o<strong>the</strong>r models tend to be more reliable: for example,some viral diseases [e.g. <strong>in</strong>fluenza, but nei<strong>the</strong>r HIV nor hepatitis-Cviral (HCV) <strong>in</strong>fections]; bacterial and fungal <strong>in</strong>fections; CVDthrough measur<strong>in</strong>g high- and low-density lipoprote<strong>in</strong> (HDL andLDL, respectively) and simple blood chemistry-based readouts (e.g.glucose or cholesterol). One could argue that, <strong>in</strong> a typical researchproject, 20–30% of <strong>the</strong> time is spent f<strong>in</strong>e-tun<strong>in</strong>g molecules to fit<strong>the</strong> animal model of disease ‘perfectly’. The cost of which, if<strong>in</strong>vested <strong>in</strong> a ‘fast’ proof-of-concept <strong>in</strong> <strong>the</strong> human cl<strong>in</strong>ical sett<strong>in</strong>g,could easily answer <strong>the</strong> key question. Pharmaceutical researchaimed at cancer treatment, neurological or psychiatric diseases,<strong>in</strong> particular, are areas <strong>in</strong> utmost need of new <strong>the</strong>rapeutics, yet <strong>the</strong>most underserved from <strong>the</strong> <strong>discovery</strong>-to-cl<strong>in</strong>ical-success standpo<strong>in</strong>t.As mentioned above, animal models <strong>in</strong> <strong>the</strong>se disease areasare not predictive, yet regulatory agencies require precl<strong>in</strong>ical<strong>in</strong>vestigational new drug (IND) packages to conta<strong>in</strong> <strong>in</strong> vivo animalefficacy and data based on nonpredictive or nonrelevant diseasemodels. It is sad to see that many companies are giv<strong>in</strong>g up on <strong>the</strong>sediseases ra<strong>the</strong>r than tackl<strong>in</strong>g <strong>the</strong> fundamental biological, pharmacologicaland developmental causes of <strong>the</strong> failures. Perhaps <strong>the</strong><strong>in</strong>dustry needs to tackle this very problem to demonstrably affectchange <strong>in</strong> <strong>the</strong> success rate of oncolytics, neurological agents orneuroleptics, to name but a few.Given that <strong>the</strong> goal of animal pharmacology drug <strong>discovery</strong> is todemonstrate target engagement <strong>in</strong> liv<strong>in</strong>g species, with functionalconsequence and m<strong>in</strong>imal adverse effects, fur<strong>the</strong>r research <strong>in</strong> morevariants of humanized mice will probably help <strong>in</strong> this area [57–64].So how, and when, should animal pharmacology be best <strong>in</strong>tegrated,if at all, go<strong>in</strong>g forward?Toxicology-based advancesCurrently, <strong>the</strong> greatest contributors to precl<strong>in</strong>ical and cl<strong>in</strong>icalNME failures rema<strong>in</strong> toxicology and translational biology forefficacy. Strik<strong>in</strong>g <strong>the</strong> right <strong>the</strong>rapeutic w<strong>in</strong>dow, with a safe profileis often a challenge <strong>in</strong> <strong>discovery</strong> sett<strong>in</strong>gs. Much research is be<strong>in</strong>gapplied to br<strong>in</strong>g value from <strong>the</strong> toxicological standpo<strong>in</strong>t: forexample, screen<strong>in</strong>g for mutagens, clastogens and general cellulartoxicities [cytotoxicity panels, hepatocytes, phospholipidosis,transporters and human-e<strong>the</strong>r-a-go-go related gene channel(hERG) blockade], <strong>in</strong> silico predictions of toxicophores, rapid earlyanimal-based toxicological readouts and multi-species cardiovascularreadouts [65–67]. The field is still plagued by cl<strong>in</strong>ical idiosyncratictoxicities, particularly <strong>in</strong> comb<strong>in</strong>ation sett<strong>in</strong>gs where druglevels suffer from output from metaboliz<strong>in</strong>g enzymes and <strong>the</strong>irputative effects on many organs. Much effort is <strong>needed</strong> to predictaccurately patient safety outcomes through precl<strong>in</strong>ical screen<strong>in</strong>g.Therefore, how can <strong>the</strong> <strong>in</strong>dustry, <strong>in</strong> a similar manner to thatachieved <strong>in</strong> PK (less of a contributor to cl<strong>in</strong>ical drug attrition),maximize translational safety or m<strong>in</strong>imize idiosyncratic toxicityfrom NMEs?So far, I have highlighted <strong>the</strong> necessity for <strong>in</strong>novation, <strong>the</strong>perspective of how <strong>in</strong>vestor pressure has led <strong>the</strong> <strong>in</strong>dustry to whereit currently is, and <strong>the</strong> advances and challenges of all <strong>the</strong> necessaryscientific discipl<strong>in</strong>es that harbor and feed <strong>in</strong>to medic<strong>in</strong>al chemistry.Several questions were raised but not answered. The wholeconcept of <strong>the</strong> culture of <strong>in</strong>novation <strong>in</strong> <strong>the</strong> drug <strong>discovery</strong> sett<strong>in</strong>grema<strong>in</strong>s nebulous, given <strong>the</strong> multitude of ‘pressure po<strong>in</strong>ts: <strong>in</strong>vestment,competition, science knowledge, time, management’, <strong>the</strong>diversity of sources of <strong>in</strong>novation and <strong>the</strong> still-unpredictablenature of medic<strong>in</strong>al chemistry, drug <strong>discovery</strong> and cl<strong>in</strong>ical outcomes[68–70].IntegrationDespite <strong>the</strong> advances, and <strong>the</strong> challenges ahead <strong>in</strong> <strong>the</strong> various drug<strong>discovery</strong> discipl<strong>in</strong>es, <strong>the</strong>ir <strong>in</strong>tegration <strong>in</strong>to a functional, timelyand productive output is an open question. The above-mentionedstatement by Jenssen captures <strong>the</strong> essence of a major pitfall ofcurrent drug <strong>discovery</strong> issues: <strong>in</strong>tegration of <strong>the</strong> above-discusseddiscipl<strong>in</strong>es. Some differences occur between academia and <strong>in</strong>dustry:for example, <strong>in</strong> graduate studies, <strong>the</strong>re is an emphasis on <strong>the</strong><strong>in</strong>dividual and not <strong>the</strong> team, and cross-department collaborationsare very new <strong>in</strong> <strong>the</strong> academic sett<strong>in</strong>g, whereas cross-departmentteamwork is important for success <strong>in</strong> <strong>in</strong>dustry; <strong>in</strong>novation isgenerally fostered <strong>in</strong> academia, yet some pharmaceutical organizationstend to redef<strong>in</strong>e <strong>the</strong> word ‘new’ as ‘me-too’ or ‘me-better’.Additionally, higher education systems are organized aroundscientific discipl<strong>in</strong>es and departments, whereas researchers naturallytend to congregate around similar models <strong>in</strong> <strong>the</strong> <strong>in</strong>dustrialsett<strong>in</strong>g. Alternatively, <strong>the</strong> <strong>in</strong>dustry tends to be organized arounddiseases or <strong>the</strong>rapeutic areas, with emphasis on centers of excellence.There are few organizational models based around ‘drug784 www.drug<strong>discovery</strong>today.com
<strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011REVIEWS<strong>discovery</strong> excellence’ or ‘<strong>in</strong>tegrated disease <strong>discovery</strong> and developmentcenters’ or, better still, ‘chemical biology–pharmacology’,‘pharmaceutics development’, and so on. The po<strong>in</strong>t here is thatmuch <strong>in</strong>novation, speed, productivity are probably lost throughlack of better <strong>in</strong>tegrative organizational, cultural and scientificcommunication models. Innovative organizational and managementmodels, along <strong>the</strong> entire spectrum of R&D, will be key <strong>in</strong>help<strong>in</strong>g address current shortcom<strong>in</strong>gs [71].The follow<strong>in</strong>g paragraphs are an attempt to capture some of <strong>the</strong>cultural attributes that are necessary to maximize <strong>the</strong> chances fornew products, with particular examples <strong>in</strong> <strong>the</strong> small-moleculeR&D sett<strong>in</strong>g. I propose i<strong>ASAP</strong> as a set of organizational behaviorsthat could help ignite <strong>in</strong>novation.Ask powerful questionsThe art of ask<strong>in</strong>g powerful questions (why, how and what are morepowerful than when, where or yes/no questions) <strong>in</strong> any researchsett<strong>in</strong>g leads to <strong>in</strong>quiry, <strong>in</strong>sight, open ideas and depth of thought. aAsk<strong>in</strong>g questions, such as how can one f<strong>in</strong>d <strong>the</strong> best treatment fordiabetes? Why do some people develop schizophrenia or Alzheimer’sdisease? Is more profound than ask<strong>in</strong>g, for example, whenare we go<strong>in</strong>g to have someth<strong>in</strong>g that works for diabetes?Ask<strong>in</strong>g powerful questions will tend to: (i) stimulate reflectiveth<strong>in</strong>k<strong>in</strong>g; (ii) challenge assumptions; (iii) shake dogma; and (iv)generate energy. This simple rule of engagement on what isimportant to work on, why is it important and how to solve it,should help researchers better channel <strong>the</strong>ir ideas. As Peter Medawarsaid: ‘any scientist of any age who wants to make importantdiscoveries must study important problems. Dull or piffl<strong>in</strong>g problemsyield dull or piffl<strong>in</strong>g answers’ [72].Organizations should work hard at, and foster, ask<strong>in</strong>g <strong>the</strong> rightquestions ra<strong>the</strong>r than be pulled by market<strong>in</strong>g demands for me-tooproducts. Although me-too medic<strong>in</strong>es provide a short-term relieffrom <strong>the</strong> f<strong>in</strong>ancial pressure of los<strong>in</strong>g market share, <strong>the</strong>y foster aculture of <strong>in</strong>novation complacency. Organizationally, hav<strong>in</strong>gteams of ‘scary-smart’ scientists is necessary, but not sufficientfor <strong>in</strong>novation: talented scientists need to be channeled <strong>in</strong>toask<strong>in</strong>g <strong>in</strong>spir<strong>in</strong>g questions, for <strong>the</strong> right results to happen. Thisis a fundamental difference between drug hunt<strong>in</strong>g (or mak<strong>in</strong>gmedic<strong>in</strong>es that work <strong>in</strong> humans) as opposed to ‘academic work’,where great science might be done, often without immediateapplicability to human pathology.Rules are barriers to <strong>in</strong>novationCurrently, much effort is be<strong>in</strong>g devoted to retrospective databasem<strong>in</strong><strong>in</strong>g (literature and patents) to encode knowledge and f<strong>in</strong>d <strong>the</strong>cure to pharmaceutical product drought. These exercises rangefrom understand<strong>in</strong>g what constitutes a ‘perfect’ drug space, whatphysicochemical attributes drive good pharmacok<strong>in</strong>etic outcomes(which does not necessarily translate well across species) throughPKPD predictive model<strong>in</strong>g and allometric scal<strong>in</strong>g, to m<strong>in</strong>imiz<strong>in</strong>gidiosyncratic toxicity and def<strong>in</strong><strong>in</strong>g <strong>the</strong> physicochemical propertiesof blood–bra<strong>in</strong> barrier-penetrat<strong>in</strong>g compounds [73]. Rules area The word ‘powerful’ can be substituted by: relevant, prob<strong>in</strong>g, <strong>in</strong>quisitive,provocative, <strong>in</strong>cisive, bold, thought-provok<strong>in</strong>g. See Vogt, E.E. et al. The Art ofPowerful Questions: Catalys<strong>in</strong>g Insight, Innovation, and Action; for pdf article:http://www.<strong>the</strong>worldcafe.com/articles/aopq.pdf.<strong>in</strong>herently deductive; that is, <strong>the</strong>y break down data, behaviorsor thought processes <strong>in</strong>to discrete measurable bundles of activitythat can <strong>the</strong>n be ordered, thus lead<strong>in</strong>g to answers. Although thiscan be value add<strong>in</strong>g, bl<strong>in</strong>dly follow<strong>in</strong>g rules and guidel<strong>in</strong>es canalso lead to ‘bl<strong>in</strong>dness’ (whereas scientifically based, <strong>the</strong>se guidel<strong>in</strong>eshave to be taken with a gra<strong>in</strong> of salt). Given that rules comefrom retrospective analyses, <strong>the</strong>y can stifle creativity and serve asbarriers to future breakthrough <strong>in</strong>novations. Rules, <strong>in</strong> general,tend to suppress <strong>the</strong> ‘<strong>in</strong>dividual’ and many medic<strong>in</strong>es are ‘<strong>in</strong>dividuals’operat<strong>in</strong>g <strong>in</strong> exception or outlier space. Rules- or guidel<strong>in</strong>esbaseddrug <strong>discovery</strong> does fit with<strong>in</strong> current understand<strong>in</strong>g ofprocess and, as such, is a manager’s dream. It does not requiremuch creativity to follow a set of guides, or standard operat<strong>in</strong>gpr<strong>in</strong>ciples previously worked out to generate data. Is part of <strong>the</strong>problem that we, as a society, have learned to live with <strong>the</strong>crutches of technology, where everyth<strong>in</strong>g is <strong>in</strong> ‘kit’ form and<strong>the</strong> underly<strong>in</strong>g pr<strong>in</strong>ciples and processes are no longer understood(or worse) cared about?Ano<strong>the</strong>r aspect <strong>in</strong> drug <strong>discovery</strong> is that of contradictions, if oneonly paid attention to <strong>the</strong>m. As examples: Many anil<strong>in</strong>es are mutagenic yet many successful drugs conta<strong>in</strong>anil<strong>in</strong>es, <strong>in</strong>clud<strong>in</strong>g <strong>the</strong> best-sell<strong>in</strong>g drug worldwide, Lipitor. Excellent team work is at <strong>the</strong> heart of successful drug <strong>discovery</strong>,yet success requires <strong>the</strong> extraord<strong>in</strong>ary contributions of <strong>in</strong>dividuals. Productivity is crucial to success, yet quantitative goals aretypically mean<strong>in</strong>gless. Performance is measured on an annual basis and is metricbased, even down to <strong>the</strong> number of assays run, yet true progressof research is completely <strong>in</strong>dependent of ei<strong>the</strong>r <strong>the</strong> calendar orsuch metrics.Science should move ahead through both <strong>in</strong>tegration of <strong>the</strong> pastand observation of <strong>the</strong> unusual, valu<strong>in</strong>g contradictions [74], aswell as directed powerful question<strong>in</strong>g. So why does <strong>the</strong> <strong>in</strong>dustry,follow sets-of-rules so diligently, ra<strong>the</strong>r than explore <strong>the</strong> more<strong>in</strong>novative outlier space?Seek <strong>the</strong> outliersOutliers, as def<strong>in</strong>ed here, are a composite of key <strong>in</strong>dividuals, teams,observations, research approaches, work environment, corporatetolerance for, and re<strong>in</strong>forcement of, different perspectives, adequatereward systems and <strong>the</strong> ability to seize those ‘aha’ moments:<strong>in</strong>novation is all about culture. Outliers are not necessarily <strong>in</strong>dividualcontributors; <strong>the</strong>y are observations, unique data relationshipsthat do not fit <strong>the</strong> hypo<strong>the</strong>sis or dogma, or that cause areth<strong>in</strong>k of assumptions [72].Individual outliers and outlier teamsGood <strong>in</strong>novators are good problem solvers (who might or mightnot be outliers), skilled <strong>in</strong> <strong>the</strong> art of visual observation, data<strong>in</strong>tegration and listen<strong>in</strong>g. Their ability to identify <strong>the</strong> right need,through powerful question<strong>in</strong>g, will naturally lead to value-creat<strong>in</strong>gideas, concepts, solutions and, eventually, products. ‘Rational’problem-solv<strong>in</strong>g <strong>the</strong>ories lead<strong>in</strong>g to practical techniques [75] aresuccessfully used <strong>in</strong> various <strong>in</strong>dustrial sett<strong>in</strong>gs [76]. However, <strong>the</strong>concept of ‘gut feel<strong>in</strong>g’ is also present to some extent <strong>in</strong> <strong>the</strong> drug<strong>discovery</strong> environment [77]. It is generally associated with key<strong>in</strong>dividuals who, for some reason, end up ei<strong>the</strong>r mak<strong>in</strong>g <strong>the</strong> bestReviews KEYNOTE REVIEWwww.drug<strong>discovery</strong>today.com 785
REVIEWS <strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011[(Figure_5)TD$FIG]Reviews KEYNOTE REVIEWOOOH 2NAliskiren®OH OFIGURE 5<strong>Drug</strong>s with unusual physicochemical characteristics and high medical value.HNNH 2 NNONOOONHOHOOHONNNOOO NHNNOOCylospor<strong>in</strong>®<strong>Drug</strong> Discovery Todaymolecules or lead<strong>in</strong>g o<strong>the</strong>rs <strong>in</strong> <strong>the</strong> right direction of key problemsolv<strong>in</strong>g. Although much effort has been directed toward fitt<strong>in</strong>gb<strong>in</strong>ary codes to many pieces of <strong>the</strong> <strong>discovery</strong> puzzle throughdatabase m<strong>in</strong><strong>in</strong>g or knowledge encod<strong>in</strong>g to identify why some<strong>in</strong>dividuals ‘just get it’, <strong>the</strong> answer rema<strong>in</strong>s elusive [78,79].Benchmark<strong>in</strong>gOne of <strong>the</strong> key issues currently fac<strong>in</strong>g scientists and drug hunters(not all outliers) is <strong>the</strong> simple fact that <strong>the</strong>y do not know what <strong>the</strong>ydo not know. Too often, <strong>the</strong> problem is over-<strong>in</strong>tellectualized, andonly <strong>the</strong> very powerful questions are asked, ra<strong>the</strong>r than <strong>the</strong> ‘wonderquestions’, such as ‘why not?’, ‘have we considered?’ and ‘Iwonder’ about how someth<strong>in</strong>g works, or ought to or could work? Itis important to remember that most, if not all, scientists thrive onsolv<strong>in</strong>g great problems and live to tackle big challenges. Althoughit is important to observe <strong>the</strong> present and study <strong>the</strong> past, benchmark<strong>in</strong>gcan be dangerous <strong>in</strong> lead<strong>in</strong>g to only <strong>in</strong>crementally <strong>in</strong>ventiveproducts. The drug <strong>discovery</strong> bus<strong>in</strong>ess, just like every o<strong>the</strong>rone, requires <strong>in</strong>tense teamwork. Teams need not comprise onlyoutliers, but should have some onboard and pay attention to <strong>the</strong>irperspectives. Benchmark<strong>in</strong>g one’s strategies, projects, teams andefforts is a futile exercise, as it generally leads to duplicative andnon<strong>in</strong>ventive work.<strong>Drug</strong>s fall<strong>in</strong>g under ‘outlier space’Given <strong>the</strong> current success rate from conception to market, whichcould easily be qualified to be 1%, for most drug projects, one canassume that <strong>the</strong> drug <strong>discovery</strong> <strong>in</strong>dustry operates <strong>in</strong> <strong>the</strong> outlierspace, <strong>in</strong> general, of what is typically acceptable <strong>in</strong> many o<strong>the</strong>r<strong>in</strong>dustries.In small-molecule drug <strong>discovery</strong>, ‘high probability chemicaland/or drug space’ can be def<strong>in</strong>ed by <strong>the</strong> properties that correlatewith successful drugs; whereas ‘outlier space’ can be def<strong>in</strong>ed asspace fall<strong>in</strong>g outside <strong>the</strong> 90% cluster between any three or four of<strong>the</strong> follow<strong>in</strong>g parameters: partition coefficient (Log P), molecularweight (MW), hydrogen bond donor (HBD), hydrogen bondacceptor (HBA), polar surface area (PSA), solubility, potency, permeability,absorption, and so on, <strong>in</strong> a 3D relationship. In o<strong>the</strong>rwords, ‘outlier space’ def<strong>in</strong>es molecules hav<strong>in</strong>g one or two keyproperties ly<strong>in</strong>g <strong>in</strong> ‘non-conform<strong>in</strong>g’ space. This space can be‘populated’ by unusually effective drugs, despite <strong>the</strong>ir ‘non-fitt<strong>in</strong>g’properties, or <strong>the</strong>ir pharmacok<strong>in</strong>etic-disposition profiles ormechanism of action, that fall outside <strong>the</strong> ‘norm’. Several valuablemedic<strong>in</strong>es tend to fall under <strong>the</strong> outlier space ra<strong>the</strong>r than meet all<strong>the</strong> ‘rules’. Here are just a few examples: Aliskiren 1 [Fig. 5; MW, 551; PSA, 146, HBA, 23; human %F(percentage oral bioavailability), 3; T 1/2 , 40 hours; bioavailabilityis limited by low permeability, PGP efflux and first-passhepatic extraction; potent drug on ren<strong>in</strong>, high dose effective,exposure variability tolerated] [80]. Cyclospor<strong>in</strong> 1 (Fig. 5; MW, 1202; PSA, 287; Log P, 14.3; HBD, 6;orally absorbed by passive diffusion, requires microemulsionformulation, approved and valuable for patients) [81]. All natural product-based drugs [Lovenox 1 , Oxycont<strong>in</strong> 1 ,Taxotere 1 , Tacrolimus 1 , Pulmicort 1 and Nasonex 1 (qu<strong>in</strong>onesteroids) (Fig. 6); erythromyc<strong>in</strong>-based antibiotics, b-lactambasedantibiotics etc.] fall with<strong>in</strong> this outlier space, given thatmolecules of such beauty or complexity are not usuallydesigned [82–84]. Nature seems to strike <strong>the</strong> right balancebetween potency, selectivity and physicochemical properties,tak<strong>in</strong>g full advantage of metaboliz<strong>in</strong>g enzymes and transporterswhen <strong>needed</strong>. She also takes time to make such exquisitelybeautiful and effective molecules and tests and ref<strong>in</strong>es <strong>the</strong>mextensively [85]. Some outlier molecules, which would tend to be avoided <strong>in</strong>current design projects; for example, S<strong>in</strong>gulair 1 , Plavix 1(Fig. 7) and Nexium 1 , which all label prote<strong>in</strong>s <strong>in</strong> vivo [86];Zetia 1 (conta<strong>in</strong>s a b-lactam, not <strong>in</strong>volved <strong>in</strong> <strong>the</strong> mechanism ofaction) [87] and Velcade 1 , which conta<strong>in</strong>s a boronic acid [88],also form ano<strong>the</strong>r outlier group. Several molecules, currently undergo<strong>in</strong>g cl<strong>in</strong>ical trials, suchTelaprevir 1 (HCV protease <strong>in</strong>hibitor with MW of 680, peptidomimetic,orally bioavailable and safe and efficacious <strong>in</strong> patientswith HCV) [89,90]; or <strong>the</strong> effective cancer <strong>the</strong>rapeutic Lupron 1(a peptide, depot formulation, has high efficacy and results <strong>in</strong>excellent f<strong>in</strong>ancial returns) [91]. Many o<strong>the</strong>r examples can befound, <strong>in</strong>clud<strong>in</strong>g peptide antibiotics (e.g. Cubic<strong>in</strong> 1 [92]) andantifungals (e.g. Cancidas 1 [93]) (Fig. 8).One could also argue that molecules <strong>in</strong> <strong>the</strong> ‘outlier space’ willtend to be harder for follow-on programs and lead <strong>the</strong> way tomarket with m<strong>in</strong>imal competition (one exception be<strong>in</strong>g <strong>the</strong>ATPase proton pump <strong>in</strong>hibitors). More precisely, researchers tend786 www.drug<strong>discovery</strong>today.com
<strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011[(Figure_6)TD$FIG]REVIEWSOONaO ONa SO ONaO OO OOOHOHOO NHOO O OH S OO ONaSO O SONaONaOOnHOONOHOO ONHOHO S ONaOOHOHOOHOHOHHOOHHNOOHOOOHOHHN O HO HOHO O OOOOLovenox® Oxycont<strong>in</strong>® Taxotere®OOOOOHH OOTacrolimus®OPulmicort®OOOOClHHClOHNasonex®OOReviews KEYNOTE REVIEWROONOOOHOHOOOO OOOR = H; Rapamune®R = C(O)C(CH 3)(CH 2OH) 2; Torisel®<strong>Drug</strong> Discovery TodayFIGURE 6Representative examples of drugs from natural sources.to seek <strong>the</strong> perfect prototype as early as <strong>the</strong> hit-to-lead stage, whichboxes <strong>the</strong>m early on <strong>in</strong>to a set of operational constra<strong>in</strong>ts thatmight not help <strong>in</strong> answer<strong>in</strong>g <strong>the</strong> ‘big’ question orig<strong>in</strong>ally asked.Some of <strong>the</strong> reasons for this might be both <strong>the</strong> classic ones, such asselectivity, toxicity, target validation, biology–cl<strong>in</strong>ical translationor, alternatively, that researchers are not good observers of outlierspace. <strong>Drug</strong> <strong>discovery</strong> researchers usually average toward <strong>the</strong>[(Figure_7)TD$FIG]middle or safe ground, and like deductive rules because <strong>the</strong>y areeasy to understand, safe, and anyone can follow <strong>the</strong>m.Sources of <strong>in</strong>novationWhere does one f<strong>in</strong>d problems? Not where answers already exist.As such, fast-follower- or ‘me-too’-type programs do not reallyconstitute a new scientific or medical problem to be solved. ThisHOOCISOCINSOHONOOONNNH 2NNOS<strong>in</strong>gulair®Plavix®Hytr<strong>in</strong>®<strong>Drug</strong> Discovery TodayFIGURE 7Examples of highly effective, commercially successful drugs that label prote<strong>in</strong>s <strong>in</strong> vivo.www.drug<strong>discovery</strong>today.com 787
REVIEWS <strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011[(Figure_8)TD$FIG]Reviews KEYNOTE REVIEWNOH 2 NNHONHOHOHHNNOHTelaprevir®OHNONOHOHHNO OH 2 NHNHNONHOHONHONHHHN N OHOOOHOHOHNHOHNNONHNHONHHNONHONHNHONHOHOHNLupron®CONH 2 OOHNNOHCO 2 HOHONHOHNO O NHNOOHNHHNNH 2H 2 NOHONNN ONH H O HHNHO 2 C HO2 C OO O HO NHOHNN N OHHOONH 2 HO OHOCancidas®Cubic<strong>in</strong>®<strong>Drug</strong> Discovery TodayFIGURE 8Representative examples of peptide-based or peptido-mimetic cl<strong>in</strong>ical agents or successful drugs.careful selection of endeavor promotes research <strong>in</strong> areas where<strong>the</strong>re is less competition, which means more time to search a widerarea.Szent-Gyorgyi [72] advises one to renew old knowledge, andseveral classic stories come to m<strong>in</strong>d here. For example, rapamyc<strong>in</strong>was toxic to animals, which put a halt to <strong>the</strong> project dur<strong>in</strong>g <strong>the</strong>mid-1970s. Almost 20 years later, <strong>the</strong> immunosuppressant propertiesof this natural product were biologically better understood,pav<strong>in</strong>g <strong>the</strong> way to two approved drugs <strong>in</strong> immunology (Rapamune1 ) [94] and oncology (Torisel 1 ) [95]; Thalidomide 1 , orig<strong>in</strong>allyapproved as an antiemetic agent, was removed from <strong>the</strong>cl<strong>in</strong>ical sett<strong>in</strong>g, but later found approved use <strong>in</strong> oncology [96];Hytr<strong>in</strong> 1 (Fig. 7), orig<strong>in</strong>ally developed as antihypertensive agent,later found use as a treatment for benign prostate hyperplasia [97].Each R&D organization has a wealth of historical, corporateresearch knowledge to tap <strong>in</strong>to, and too much of this is likelyto be go<strong>in</strong>g untouched and/or unexam<strong>in</strong>ed.By contrast, Pasteur’s method [72] is to f<strong>in</strong>d contradictionbetween <strong>the</strong>ory, or dogma, and data. A particularly <strong>in</strong>terest<strong>in</strong>gand potentially valuable measure of discoveries is a contradictionbetween what was expected and <strong>the</strong> newly generated data, whereone or o<strong>the</strong>r must be wrong; <strong>in</strong> such situations, someth<strong>in</strong>g usefulcan usually be learned. A classic example is <strong>the</strong> <strong>discovery</strong> of Zetia 1 ,where <strong>the</strong> team was target<strong>in</strong>g acetyl-coenzyme A acetyltransferase(ACAT) <strong>in</strong>hibitors; however, no correlation was observed betweencompound <strong>in</strong>hibitory concentration on ACAT and <strong>in</strong> vivo efficacy <strong>in</strong>lower<strong>in</strong>g cholesterol absorption [54]. Follow<strong>in</strong>g <strong>the</strong> <strong>in</strong> vivo efficacystructure–activity relationship (SAR), led to this important <strong>discovery</strong>and, subsequently, to <strong>the</strong> identification of its trans-membranecholesterol transporter prote<strong>in</strong>. The contradiction is obvious <strong>in</strong> thiscase: shallow <strong>in</strong> vitro SAR, with <strong>in</strong>verse correlation to <strong>in</strong> vivo efficacy.Langmuir’s pr<strong>in</strong>ciple [72] was to simply turn <strong>the</strong> problem on itshead: ‘Sometimes nei<strong>the</strong>r serendipity nor plann<strong>in</strong>g cooperateswith <strong>the</strong> desires of <strong>the</strong> scientists’. When a desired effect is h<strong>in</strong>deredby various <strong>in</strong>terfer<strong>in</strong>g factors, one should deliberately focus on <strong>the</strong>undesirable factors so as to exaggerate or understand <strong>the</strong>ir badeffects. Perhaps someth<strong>in</strong>g new will be uncovered as a result. As anexample, erythromyc<strong>in</strong>, one of <strong>the</strong> first successful macrolide antibiotics,had a side effect that resulted <strong>in</strong> gastro<strong>in</strong>test<strong>in</strong>al motility.It turned out that <strong>the</strong> culprit was not erythromyc<strong>in</strong> itself, but arearrangement derivative (hemiketal furan) produced, under <strong>the</strong>low pH of <strong>the</strong> stomach, which activated motil<strong>in</strong> receptors, thuslead<strong>in</strong>g to gastro<strong>in</strong>test<strong>in</strong>al movement [98]. Capitaliz<strong>in</strong>g on this‘side effect’ led to research <strong>in</strong>to motil<strong>in</strong> agonists for <strong>the</strong> treatmentof both gastroesophageal reflux disease and diabetic gastroparesis,and <strong>the</strong> <strong>discovery</strong> of <strong>the</strong> motil<strong>in</strong> receptor [99–101].Outliers can be successfulIn his book Outliers: The Story of Success, Malcolm Gladwell arguesthat success is attributed to exceptional people and those whooperate at <strong>the</strong> extreme outer edge of what is statistically possible[102]. Identify<strong>in</strong>g coworkers with such skills and provid<strong>in</strong>g just <strong>the</strong>right environment for <strong>the</strong>m to operate will undoubtedly lead tovaluable <strong>in</strong>novation.788 www.drug<strong>discovery</strong>today.com
<strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011REVIEWSAno<strong>the</strong>r analogy can be drawn from <strong>the</strong> bus<strong>in</strong>ess strategymantra: Blue Ocean Strategy. In <strong>the</strong> latter, <strong>the</strong> metaphor of redand blue oceans describes <strong>the</strong> market universe [103].‘Red Oceans are all <strong>the</strong> <strong>in</strong>dustries <strong>in</strong> existence today—<strong>the</strong>known market space. In <strong>the</strong> red oceans, <strong>in</strong>dustry boundariesare def<strong>in</strong>ed and accepted, and <strong>the</strong> competitive rulesof <strong>the</strong> game are known. Here companies try to outperform<strong>the</strong>ir rivals to grab a greater share of product or servicedemand. As <strong>the</strong> market space gets crowded, prospects forprofits and growth are reduced. Products become commodities,and cutthroat competition turns <strong>the</strong> oceanbloody. Blue oceans, <strong>in</strong> contrast, denote all <strong>the</strong> <strong>in</strong>dustriesnot <strong>in</strong> existence today—<strong>the</strong> unknown market space,unta<strong>in</strong>ted by competition. In blue oceans, demand iscreated ra<strong>the</strong>r than fought over. There is ample opportunityfor growth that is both profitable and rapid. In blueoceans, competition is irrelevant because <strong>the</strong> rules of <strong>the</strong>game are wait<strong>in</strong>g to be set. Blue Ocean is an analogy todescribe <strong>the</strong> wider, deeper potential of market space thatis not yet explored.’ (http://en.wikipedia.org/wiki/Blue_Ocean_Strategy).Apply<strong>in</strong>g <strong>the</strong> above metaphor to drug <strong>discovery</strong> becomes selfexplanatory,and <strong>in</strong>vites <strong>in</strong>novators to chart new ‘Blue ocean-likedrug <strong>discovery</strong>’ maps, where competition is lower, but risk andreward are higher, yet more value-creat<strong>in</strong>g (Fig. 9). Although <strong>the</strong>above perspective might have a ‘pie-<strong>in</strong>-<strong>the</strong>-sky’ sentiment to it,practitioners <strong>in</strong> drug <strong>discovery</strong> and development, as well as executivemanagement teams, need to th<strong>in</strong>k hard about <strong>the</strong> future ofwhere <strong>the</strong>ir <strong>in</strong>vestment activities need to be. Duplication, <strong>in</strong>strategy and scientific endeavor, of what has happened over <strong>the</strong>past two <strong>decade</strong>s will be futile, if not <strong>in</strong>cremental. There rema<strong>in</strong>many seriously underserved diseases [e.g. cancer (all forms), schizophrenia,depression, multiple sclerosis, Park<strong>in</strong>son’s, Alzheimer’s,Hunt<strong>in</strong>gton’s and amyotrophic lateral sclerosis (ALS)diseases; <strong>in</strong>fectious diseases (<strong>in</strong>fluenza, gram-negative bacterial<strong>in</strong>fections), cystic fibrosis, and many more]; that will require[(Figure_9)TD$FIG]Red oceandrug <strong>discovery</strong>Blue oceandrug <strong>discovery</strong><strong>Drug</strong> Discovery TodayFIGURE 9Representation of i<strong>ASAP</strong> ‘property space’ by analogy to <strong>the</strong> classic Log P–PSAgraph for ‘drug space’. The X-axis <strong>in</strong>dicates risk/reward, whereas <strong>the</strong> Y-axis<strong>in</strong>dicates <strong>in</strong>novation.new approaches. Attack<strong>in</strong>g <strong>the</strong>se diseases, with novelty, patienceand vigor, will undeniably create opportunities for corporationsto reap f<strong>in</strong>ancial benefits. The red ocean has been tried and it istime to discover new ‘territories’. A complementary perspectivecover<strong>in</strong>g <strong>discovery</strong> management, corporatesizeandwhyfailureto understand scientists’ psyche and motivational drivers hascontributed to drug R&D failure has recently been published[104].So how do we set ourselves up for success?Scientists must become better observers and listeners. As examples:(i) much creative th<strong>in</strong>k<strong>in</strong>g happens at <strong>the</strong> more junior levels <strong>in</strong>organizations (fresh th<strong>in</strong>k<strong>in</strong>g). Promot<strong>in</strong>g such behavior and f<strong>in</strong>d<strong>in</strong>gmechanisms to exploit it rapidly, without middle-managementstifl<strong>in</strong>g, is likely to pay dividends; (ii) many mistakes,mishaps, or difficulties occur <strong>in</strong> <strong>the</strong> execution of any projectand, if properly observed and astutely questioned (why, how,what), could create a new momentum; (iii) a disgruntled coworkermight be suggest ways to change standard operat<strong>in</strong>g procedures;(iv) a repeat-failure might be suggest<strong>in</strong>g reposition<strong>in</strong>g for a newsystem; and (v) an untreated or ill-treated disease signals <strong>the</strong> needfor an entirely new paradigm, as is <strong>the</strong> case for Rapamyc<strong>in</strong> (Rapamuneand Torisel) (Fig. 6) and Hytr<strong>in</strong> (Fig. 7).Accept defeat, <strong>the</strong>n go back‘If you can meet with Triumph and DisasterAnd treat those two imposters just <strong>the</strong> same’: RudyardKipl<strong>in</strong>g, from his poem ‘‘If’’.It might appear that <strong>in</strong>ventiveness is a personality trait, rooted<strong>in</strong> <strong>the</strong> bra<strong>in</strong>, and that is part of an <strong>in</strong>quisitive personality. Thedesire to seek <strong>the</strong> better, more efficient, ‘never-discovered’approach is generally revered and could be attributed to only afew <strong>in</strong>dividuals. However, all <strong>in</strong>ventors will easily admit <strong>the</strong>y‘almost’ quit many times on any given project, and thus potentiallymiss<strong>in</strong>g important <strong>in</strong>ventions. In <strong>the</strong> process of com<strong>in</strong>g upwith a ‘new th<strong>in</strong>g or idea’, one will need to accept failure as par for<strong>the</strong> course and not get discouraged. In <strong>the</strong> bus<strong>in</strong>ess of <strong>in</strong>novation,one could argue that character, <strong>the</strong> ability to deal with failure, ismore important than <strong>in</strong>tellect. The challenge here is that mostscientists are tra<strong>in</strong>ed to persevere (and not accept defeat) <strong>in</strong> <strong>the</strong>face of negative research outcome, which makes this a harder caseto deal with.The ability to both accept defeat and manage plans mov<strong>in</strong>gforward is essential to keep<strong>in</strong>g goals <strong>in</strong> check. In The Neuroscience ofScrew<strong>in</strong>g Up, Jonah Lehrer eloquently describes how <strong>the</strong> ability torecognize when to give up, helps one see challenges <strong>in</strong> a verydifferent way than before [105]. He cites several examples, <strong>in</strong>clud<strong>in</strong>g<strong>the</strong> story beh<strong>in</strong>d <strong>the</strong> physics lead<strong>in</strong>g <strong>the</strong> Big Bang <strong>the</strong>ory andaward<strong>in</strong>g Penzias and Wilson <strong>the</strong> 1978 Nobel Prize <strong>in</strong> physics.In <strong>the</strong> drug <strong>discovery</strong> bus<strong>in</strong>ess, researchers are ‘wrong’ approximately90% of <strong>the</strong> time on precl<strong>in</strong>ical candidates and on 90% of<strong>the</strong> projects (as measured by NCEs <strong>in</strong>to <strong>the</strong> cl<strong>in</strong>ic). Compoundrelatedattrition ow<strong>in</strong>g to PK or toxicology; disconnects betweenbiological target and disease; lack of proper cl<strong>in</strong>ical efficacy, targetbasedtoxicity or cl<strong>in</strong>ical trial design problems, generally contributeto <strong>the</strong>se failure rates. Additional contributions to this m<strong>in</strong>imalReviews KEYNOTE REVIEWwww.drug<strong>discovery</strong>today.com 789
REVIEWS <strong>Drug</strong> Discovery Today Volume 16, Numbers 17/18 September 2011Reviews KEYNOTE REVIEWsuccess can be strategic, organizational, tactical or cultural <strong>in</strong> nature.I do not argue for giv<strong>in</strong>g up early, but ra<strong>the</strong>r for appreciat<strong>in</strong>g <strong>the</strong> netpositive effect of ‘accept<strong>in</strong>g be<strong>in</strong>g wrong’, early. Despite all <strong>the</strong>plann<strong>in</strong>g and assurance, one can be wrong at any stage. Such anacceptance will lead to m<strong>in</strong>d-openness and <strong>the</strong> ability to see clearerand hopefully m<strong>in</strong>imize error-repeat. As thoroughly described <strong>in</strong><strong>the</strong> drug <strong>discovery</strong> bus<strong>in</strong>ess, <strong>the</strong> cost of failure is high.The key here is ‘directional problem solv<strong>in</strong>g’; are <strong>the</strong> rightquestion(s) be<strong>in</strong>g asked (here it is important to have hypo<strong>the</strong>sesand not just open-ended questions) and are <strong>the</strong> results mov<strong>in</strong>g <strong>the</strong>team <strong>in</strong> <strong>the</strong> direction that <strong>the</strong>y need to go? When that stopshappen<strong>in</strong>g, it is imperative to question whe<strong>the</strong>r <strong>the</strong> team hastruly failed or has reached <strong>the</strong> limits of its current ability to moveforward: for those scientists who have a hard time lett<strong>in</strong>g go, ei<strong>the</strong>ruse <strong>the</strong> concept of ‘back-burner<strong>in</strong>g’, where <strong>the</strong> project can simmerbut not distract, or park it altoge<strong>the</strong>r.Populate astutelyLiterature on sources of <strong>in</strong>novation reveals that most <strong>in</strong>fluentialhigh-value <strong>in</strong>ventions and/or bus<strong>in</strong>ess ideas were produced by atleast two people (not one, as is commonly believed). Examplesabound <strong>in</strong> <strong>the</strong> bus<strong>in</strong>ess, scientific and artistic areas, <strong>in</strong>clud<strong>in</strong>g HP(Hewlett and Packard), Microsoft (Gates and Allen); Google (Paigeand Br<strong>in</strong>); Apple (Wozniak, Jobs and Wayne); <strong>the</strong> Beatles (Lennonand McCartney); DNA (Watson, Crick and Frankl<strong>in</strong>) and DNAsequenc<strong>in</strong>g (Maxim, Gilbert and Mirzabeckov); asymmetric epoxidation(Sharpless and Katsuki) and LDL metabolism (Brown andGoldste<strong>in</strong>) [105]. A study of <strong>the</strong> personal characteristics of <strong>the</strong>sepair<strong>in</strong>gs (and group<strong>in</strong>gs <strong>in</strong> research environments) po<strong>in</strong>ts to <strong>the</strong>complementary nature of those <strong>in</strong>volved and to <strong>the</strong>m hav<strong>in</strong>gasked powerful questions that led to <strong>the</strong>ir success.Of course, many important <strong>in</strong>ventions were attributed to s<strong>in</strong>gle<strong>in</strong>dividuals, but this seems to no longer be <strong>the</strong> norm, given <strong>the</strong>complexities now <strong>in</strong>volved to br<strong>in</strong>g a differentiated product tomarket and <strong>the</strong> coord<strong>in</strong>ated teamwork necessary for success. On<strong>the</strong> human resources side, a key component of hir<strong>in</strong>g or form<strong>in</strong>g anew team is strik<strong>in</strong>g a fair balance between people who disagree withyou and those that execute orders. Organizations should learn from<strong>the</strong>se studies and populate <strong>the</strong>ir various <strong>in</strong>novation <strong>in</strong>cubators with<strong>the</strong> appropriate complementary personalities to fuel future <strong>in</strong>novations.Many of <strong>the</strong> examples cited above, and probably many<strong>in</strong>ternally kept stories, add credence to this po<strong>in</strong>t of view. Additionally,many pharmaceutical organizations are experiment<strong>in</strong>gwith lower-cost drug <strong>discovery</strong> models (http://www.slate.com/id/2267688/; http://www.slate.com/id/2267342/, [106]), and scientificcrowd-sourc<strong>in</strong>g approaches, however, <strong>the</strong> future rema<strong>in</strong>s uncerta<strong>in</strong>about how truly <strong>in</strong>novative or value-add<strong>in</strong>g <strong>the</strong>se will be.Innovation <strong>in</strong> <strong>the</strong> pharmaceutical sector is very different fromthat <strong>in</strong> many o<strong>the</strong>rs (particularly non-science based bus<strong>in</strong>esses),simply because when researchers embark on a truly new project,<strong>the</strong>y generally have no idea what <strong>the</strong> f<strong>in</strong>al product will ‘look like’.Additionally, equat<strong>in</strong>g <strong>in</strong>novations among <strong>the</strong> various discipl<strong>in</strong>esof drug <strong>discovery</strong> is useless, <strong>the</strong> sum of all is much greater than <strong>the</strong>total. F<strong>in</strong>ally, research-<strong>in</strong>tensive organizations seek<strong>in</strong>g truly <strong>in</strong>novativeproducts, need to reward publicly and handsomely true<strong>in</strong>novation and <strong>in</strong>novators (teams and <strong>in</strong>dividuals), ra<strong>the</strong>r thanreward<strong>in</strong>g ‘me-too’ or ‘fast-follower’ products.SummaryThe future of <strong>the</strong> pharmaceutical <strong>in</strong>dustry rema<strong>in</strong>s bright, despitethis momentary lapse of appreciation from <strong>the</strong> bus<strong>in</strong>ess and politicalcommunities. Dramatic advances <strong>in</strong> chemistry, biology, pharmacology,PK, toxicology and medic<strong>in</strong>e have occurred dur<strong>in</strong>g <strong>the</strong>past 15 years (which is approximately <strong>the</strong> cycle time from <strong>discovery</strong>to market). This, <strong>in</strong> concert with some nurtur<strong>in</strong>g of more <strong>in</strong>novativecultures with<strong>in</strong> <strong>the</strong> <strong>in</strong>dividual companies, will result <strong>in</strong> new,improved medic<strong>in</strong>es to fight disease. Innovation is not an averag<strong>in</strong>gdown toward a middle ground of best practice, as is <strong>the</strong> traditional‘consultation’ mentality, but ra<strong>the</strong>r an expression of <strong>the</strong> <strong>in</strong>dividualityand creative strengths of each company. Apple is not Microsoft,yet both are creative and successful <strong>in</strong> different ways; <strong>in</strong>novation isnot someth<strong>in</strong>g to be processed, <strong>in</strong>stead it is to be nurtured, wateredand measured <strong>in</strong> years and not <strong>in</strong> quarters or months.In summary, I have shared here my perspective on what behavioralattributes could help move non-<strong>in</strong>novative cultures toward<strong>in</strong>novative ones, and to capitalize on <strong>the</strong>ir exist<strong>in</strong>g talent to helpreshape <strong>the</strong> pharmaceutical R&D bus<strong>in</strong>ess toward effective prosperity.By l<strong>in</strong>k<strong>in</strong>g <strong>the</strong> four components of <strong>ASAP</strong> (ask powerfulquestions; seek <strong>the</strong> outliers; accept defeat and populate astutely),one has a practical, and potentially useful, work<strong>in</strong>g formula tostimulate <strong>in</strong>novation <strong>in</strong> <strong>the</strong> research environment and beyond. As<strong>the</strong> say<strong>in</strong>g goes: ‘culture eats strategy for lunch, every time’.AcknowledgementsThe author wishes to acknowledge <strong>the</strong> editorial comments,support and valued discussions with many colleagues and friends,namely Raymond W<strong>in</strong>quist, Michael Briggs, Az<strong>in</strong> Nezami, ScottBiller, Jeremy Green, James Empfield, Pat Walters, StephenHanessian and Derek Lowe; as well as Janet Kibbee for heradm<strong>in</strong>istrative support.References b1 Hughes, B. (2010) 2009 FDA drug approvals. Nat. Rev. <strong>Drug</strong> Discov. 9, 89–922 Dorren Corbett, J. (2010) <strong>Drug</strong> approvals slipped <strong>in</strong> 2010. Wall Street J.3 Cavalla, D. and M<strong>in</strong>has, R. (2010) Does R&D pay? <strong>Drug</strong> Discov. Today 15, 2304 Williams, M. (2011) Productivity shortfalls <strong>in</strong> drug <strong>discovery</strong>: contributions from<strong>the</strong> precl<strong>in</strong>ical sciences? 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